The invention relates to new, unsaturated 14,15-cyclopropano-androstanes, their production and pharmaceutical preparations that contain these compounds.
Unsaturated 14,15-cyclopropano-androstanes of general formula I 
are described.
In general formula I, R1 is a hydrogen atom, a hydroxy group, an alkyloxy, acyloxy, aryloxy, aralkyloxy or an alkylaryloxy group, a radical xe2x80x94OCONHR9 or xe2x80x94OCOOR9 with R9 standing for a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in each case,
R2 stands for a hydrogen atom, a hydroxyl group, an alkyl, acyl, aryl, aralkyl, alkylaryl group with 1-10 carbon atoms in each case,
for a radical xe2x80x94(CH2)nCH2Y with n=0, 1 or 2, and Y stands for a fluorine, chlorine, bromine or iodine atom, for a cyano, azido or rhodano group, for a radical xe2x80x94OR10 or xe2x80x94SR10 with R10 standing for a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in each case or an acyl radical COR9 with R9 standing for an alkyl, aryl, aralkyl, or alkylaryl radical with 1-10 carbon atoms in each case, a radical xe2x80x94OR9 with R9 standing for a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in each case,
for a radical xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CH(CH2)nxe2x80x94R8 with m=0, 1, 2 or 3 and n=0, 1 or 2, and R8 stands for a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in each case or a hydroxyl group, an alkoxy group or acyloxy group with 1-10 carbon atoms in each case,
a radical xe2x80x94(CH2)oCxe2x89xa1CR11 with o=0, 1 or 2, and R11 stands for a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, an alkyl, aryl, aralkyl, alkylaryl or an acyl radical with 1-10 carbon atoms in each case,
R1 and R2, independently of one another, stand for a keto, methylene, or difluoromethylene group,
there can be a double bond between C-6 and C-7,
an xcex1- or xcex2-cyclopropane group X, indicated by X, that is shown standing for a CZ2 group with Z standing for a hydrogen, fluorine, chlorine, bromine or iodine atom, is located between C-14 and C-15,
R3 and R4, independently of one another, stand for a hydrogen atom, an xcex1- or xcex2-position alkyl group with 1-10 carbon atoms,
R5 stands for an alkyl group with 1-3 carbon atoms.
The compounds according to the invention, the new, unsaturated 14,15-cyclopropano-androstanes, have not yet been described. Their biological action is still unknown.
The object of this invention is to make available unsaturated 14,15-cyclopropano-androstanes of general formula 
and their pharmaceutically acceptable salts as well as a process for their production.
Another object is to make available pharmaceutical preparations that contain at least one compound of general formula I or their pharmaceutically acceptable salts.
In general formula I 
R1 is a hydrogen atom, a hydroxy group, an alkyloxy, acyloxy, aryloxy, aralkyloxy or an alkylaryloxy group, a radical xe2x80x94OCONHR9 or xe2x80x94OCOOR9 with R9 standing for a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in each case,
R2 stands for a hydrogen atom, a hydroxyl group, an alkyl, acyl, aryl, aralkyl or alkylaryl group with 1-10 carbon atoms in each case,
R2 stands for a radical xe2x80x94(CH2)nCH2Y with n 0, 1 or 2, and Y stands for a fluorine, chlorine, bromine or iodine atom, for a cyano, azido or rhodano group, for a radical xe2x80x94OR10 or xe2x80x94SR10 with R10 standing for a hydrogen atom, an alkyl, aryl, aralkyl, or alkylaryl radical with 1-10 carbon atoms in each case or an acyl radical COR9, with R9 standing for an alkyl, aryl, aralkyl, or alkylaryl radical with 1-10 carbon atoms in each case, a radical xe2x80x94OR9 with R9 standing for a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in each case,
for a radical xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CH(CH2)n xe2x80x94R8 with m=0, 1, 2 or 3 and n=0, 1 or 2, and R8 stands for a hydrogen atom, an alkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in each case or a hydroxyl group, an alkoxy group or acyloxy group with 1-10 carbon atoms in each case,
a radical xe2x80x94(CH2)oCxe2x89xa1CR11 with o=0, 1 or 2, and R11 stands for a hydrogen atom, a fluorine, chlorine, bromine or iodine atom, an alkyl, aryl, aralkyl, alkylaryl or an acyl radical with 1-10 carbon atoms in each case,
R1 and R2, independently of one another, stand for a keto, methylene, or difluoromethylene group,
there can be a double bond between C-6 and C-7,
an xcex1- or xcex2-cyclopropane group X, indicated by X, that is shown standing for a CZ2 group with Z standing for a hydrogen, fluorine, chlorine, bromine or iodine atom, is located between C-14 and C-15,
R3 and R4, independently of one another, stand for a hydrogen atom, an xcex1- or xcex2-position alkyl group with 1-10 carbon atoms,
R5 stands for an alkyl group with 1-3 carbon atoms.
Most preferred are
17xcex2-Hydroxy-14xcex1,15xcex1-methylen-androst-4-en-3-one (J 1193),
17xcex1-hydroxy-14xcex1,15xcex1-methylen-androst-4-en-3-one,
17xcex2-hydroxy-14xcex2,15xcex2-methylen-androst-4-en-3-one,
17xcex1-hydroxy-14xcex2,15xcex2-methylen-androst-4-en-3-one,
17xcex1-methyl,17xcex2-hydroxy-14xcex1,15xcex1-methylen-androst-4-ene-3-one,
17xcex2-methyl,17xcex1-hydroxy-14xcex1,15xcex1-methylen-androst-4-en-3-one,
17xcex1-methyl,17xcex2-hydroxy-14xcex2,15xcex2-methylen-androst-4-en-3-one,
17xcex2-methyl,17xcex1-hydroxy-14xcex2,15xcex2-methylen-androst-4-en-3-one,
17xcex2-hydroxy-6xcex1-methyl-14xcex1,15xcex1-methylen-androst-4-en-3-one,
17xcex1-hydroxy-6xcex1-methyl-14xcex1,15xcex1-methylen-androst-4-en-3-one,
17xcex2-hydroxy-6xcex1-methyl-14xcex2,15xcex2-methylen-androst-4-en-3-one,
17xcex1-hydroxy-6xcex1-methyl-14xcex2,15xcex2-methylen-androst-4-en-3-one,
17xcex2-hydroxy-7xcex1-methyl-14xcex1,15xcex1-methylen-androst-4-en-3-one,
17xcex1-hydroxy-7xcex1-methyl-14xcex1,15xcex1-methylen-androst-4-en-3-one,
17xcex2-hydroxy-7xcex1-methyl-14xcex2,15xcex2-methylen-androst-4-en-3-one,
17xcex1-hydroxy-7xcex1-methyl-14xcex2,15xcex2-methylen-androst-4-en-3-one,
17xcex2-hydroxy-14xcex1,15xcex1-methylen-androsta-4,6-dien-3-one,
17xcex1-hydroxy-14xcex1,15xcex1-methylen-androsta-4,6-dien-3-one,
17xcex2-hydroxy-14xcex2,15xcex2-methylen-androsta-4,6-dien-3-one,
17xcex1-hydroxy-14xcex2,15xcex2-methylen-androsta-4,6-dien-3-one,
17xcex1-methyl,17xcex2-hydroxy-14xcex1,15xcex1-methylen-androsta-4,6-dien-3-one,
17xcex2-methyl,17xcex1-hydroxy-14xcex1,15xcex1-methylen-androsta-4,6-dien-3-one,
17xcex1-methyl,17xcex2-hydroxy-14xcex2,15xcex2-methylen-androsta-4,6-dien-3-one,
17xcex2-methyl,17xcex1-hydroxy-14xcex2,15xcex2-methylen-androsta-4,6-dien-3-one,
17xcex2-hydroxy-7xcex1,17xcex1-dimethyl-14xcex1,15xcex1-methylen-androst-4-en-3-one,
17xcex1-hydroxy-7xcex1,17xcex2-dimethyl-14xcex1,15xcex1-methylen-androst-4-en-3-one,
17xcex2-hydroxy-7xcex1,17xcex1-dimethyl-14xcex2,15xcex2-methylen-androst-4-en-3-one,
17xcex1-hydroxy-7xcex1,17xcex2-dimethyl-14xcex2,15xcex2-methylen-androst-4-en-3-one.
The invention also relates to a process for the production of the compounds according to general formula I and their pharmaceutically acceptable salts, which is characterized in that a compound of general formula II 
in which R1, R2, R3 and R5 have the above-indicated meaning,
R4 stands for a hydrogen atom, a hydroxy group, an alkoxyl group, an acyloxy group, an alkyl group with 1-10 carbon atoms in each case,
R6 stands for a hydrogen atom, a hydroxy group, an alkoxyl group, an acyloxy group, an alkyl group with 1-10 carbon atoms in each case,
an xcex1- or xcex2-cyclopropane group X, indicated by X, that is shown representing a CZ2 group, in which Z can mean a hydrogen, fluorine, chlorine, bromine or iodine atom, is located between carbon atoms 14 and 15,
cleaves the 3,5-cyclopropane grouping with acids, whereby mineral acids, organic acids and Lewis acids are preferred, and then converts into the desired compounds of general formula I according to the methods that are known to one skilled in the art.
Subjects of this invention are pharmaceutical substances for oral, rectal, subcutaneous, intravenous or intramuscular use, which together with the commonly used vehicles and diluents can contain at least one compound of general formula I or its acid addition salts as an active ingredient.
Pharmaceutical preparations of the invention are produced with the commonly used solid or liquid vehicles and/or diluents and the generally commonly used adjuvants corresponding to the desired type of administration in a suitable dosage and in a way that is known in the art. In the case of a preferred oral form for dispensing, preferably tablets, film tablets, coated tablets, capsules, pills, powders, solutions or suspension are also prepared as a depot form.
In addition, parenteral dosage forms such as injection solutions or else suppositories are also considered.
Dosage forms as tablets can be obtained by, for example, mixing the active ingredient with known adjuvants, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents that can achieve a depot effect, such as carboxylpolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.
Coated tablets can be prepared analogously by coating cores that are produced analogously to the tablets with agents that are commonly used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. In this case, the coated tablet shell can also consist of several layers, whereby for example, the above-mentioned adjuvants are used.
To improve the taste, the solutions or suspensions with the active ingredient according to the invention can be mixed with substances such as saccharin, cyclamate or sugar and/or with flavoring substances, such as vanillin or orange extract. In addition, they can be mixed with suspension adjuvants, such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoic acid.
The preparation of capsules can be carried out by mixing pharmaceutical substance with vehicles such as lactose or sorbitol, which then are introduced into the capsules.
The production of suppositories is preferably carried out by mixing the active ingredient with suitable vehicles, such as neutral fats or polyethylene glycols or derivatives thereof.
In addition, the pharmaceutical preparation forms can be percutaneous preparation forms, e.g., transdermal therapeutic systems (TTS) or gels, sprays or ointments or intranasal preparation forms such as nose spray or nose drops.
The unsaturated 14,15-cyclopropano-androstanes of general formula I according to the invention are hormonal (gestagenic-and/or androgenic-acting) compounds.
Thus, for example, the compound of general formula I, in which R1 represents a hydroxyl group; R2, R3, R4 represent a hydrogen atom; R5 represents a methyl group; X represents a CH2 group, and the 14,15-cyclopropane ring is in xcex1-position, 17xcex2-hydroxy-14xcex1,15xcex1-methylen-androst-4-en-3-one (J 1193), is an androgen.
While the substance 17xcex2-hydroxy-14xcex1,15xcex1-methylen-androst-4-en-3-one (J 1193) with 24xc2x13% binds to the androgen receptor of the rat prostate (reference substance: 17xcex2-hydroxy-17xcex1-methyl-estra-4,9,11-trien-3-one: R 1881), there is virtually no binding to the progesterone receptor of the rabbit uterus (reference substance: progesterone). In the Hershberger Test, a significant androgenic activity could be detected, however there is very little gestagenic action in the pregnancy maintenance test. The substance 17xcex2-hydroxy-14xcex1,15xcex1-methylen-androst-4-en-3-one (J 1193) shows a pure androgenic profile of action that is almost free of gestagenic properties.
In the compounds of general formula I according to the invention, these test results open up many possibilities for birth control in men, hormone replacement therapy in men and women or the treatment of hormonally produced diseases in men and women, such as, for example, endometriosis, breast cancer or hypogonadism.